2. AE as an environmental disease
The picture of the reasons for the rapid increase in allergies and atopic diseases remains incomplete to this day. For sure it cannot be explained by genetics alone [15]. In fact, AE can potentially be seen as an environmental disease occurring in susceptible individuals [16-18]. A variety of intrinsic and extrinsic risk factors were identified to influence AE development and exacerbation (Figure 1) [19]. Intrinsic risk factors for AE include parental atopic history, filaggrin (FLG) mutations, polysensitization, decreased short chain fatty acids in the gut of children, and underlying medical conditions [20-25]. However, extrinsic factors as low microbial exposure and diversity, antibiotic exposure, urban environment, tobacco smoke exposure, stress, food, and pollutants are as important for AE development [16]. The lower and later exposure to microbes is described by the “hygiene” or “old friends” hypothesis and is associated with increased allergy prevalence [26, 27] [28]. The relationship between host and microbes is symbiotic and bacteria shape essential biological functions such as the development of a tolerogenic immune response towards commensals [29]. In line, the prevalence of AE was reported to be higher in urban than in rural areas [30]. The hygiene theory could be supported recently in a birth cohort – siblings, infections, and pet - especially dog keeping - were protective for AE [28, 31]. However, contradicting results exist on the influence of dog and cat ownership on disease development [32] [33]. Also, cesarean section birth with lower microbial exposure could recently not be confirmed to have a higher risk for AE than vaginal delivery [34], whereas very preterm birth even seems to be associated with decreased risk for AE development [20, 21]. A deeper understanding of the complex interplay between microbes and host is still needed [35]. Another environmental factor is the surrounding climate in a given location, a combination of temperature, and precipitation and therefore UV exposure and humidity [16]. Although contradicting reports exist on the influence of the single factors on AE development and exacerbation, they seem to be worth further investigation, especially in times of climate change [16, 36]. The patient’s residence also determines the exposure to air-pollutants which are associated with AE development. One major component of environmental air pollutants are Diesel exhaust particles, which triggers an itch-scratch response by binding to the aryl hydrocarbon receptor AhR [37, 38] [39]. Children seem to be more vulnerable than adults to pollution as an AE exacerbation trigger [40]. The stress level coming from the psychosocial environment is another extrinsic factor, which is correlated with disease symptom severity and exacerbation [6], leading to a vicious circle as AE is a strong psychological burden for patients [41, 42]. In line, psychological interventions had a positive effect on AE severity in a meta-analysis and were also associated with other allergic diseases [43, 44].